HIPEC treatment of peritoneal carcinomatosis in colorectal and gastric cancer Braam, Hidde

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1 UvA-DARE (Digital Academic Repository) HIPEC treatment of peritoneal carcinomatosis in colorectal and gastric cancer Braam, Hidde Link to publication Citation for published version (APA): Braam, H. J. W. (2015). HIPEC treatment of peritoneal carcinomatosis in colorectal and gastric cancer General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 03 Oct 2018

2 CHAPTER 12 Peritoneal cancer patients not suitable for cytoreductive surgery and HIPEC during explorative surgery: Risk factors, treatment options, and prognosis T.R. van Oudheusden H.J.W. Braam M.D.P. Luyer M.J. Wiezer B. van Ramshorst S.W. Nienhuijs I.H.J.T. de Hingh Annals of Surgical Oncology Apr; 22(4):

3 Chapter 12 Abstract Background Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is currently the only curative option for patients with peritoneal carcinomatosis of colorectal origin. Despite meticulous preoperative assessment, CRS and HIPEC appear to be impossible in a subset of patients at the time of surgery. This study investigated which clinical factors may identify these patients before surgery and reported on factors influencing survival. Methods All patients with PC of colorectal origin between April 2005 and November 2013 who underwent exploratory surgery to determine whether cytoreduction and HIPEC was feasible were included in this study. Details concerning preoperative patient characteristics, perioperative outcomes, treatment and survival were compared. Results In total, 350 patients with PC were referred to evaluate the possibility of CRS + HIPEC of which 268 (76.6%) underwent CRS and HIPEC and 82 (23.4%) had an open-close procedure. The main reason for discontinuing surgery was widespread peritoneal disease (50%). A preoperative ostomy and an ASA score of 3 were associated with an increased risk for open and close (O&C). Median survival was 11.2 months in patients treated with palliative chemotherapy (75%) compared with 2.7 months with palliative care only. Conclusions CRS and HIPEC were deemed unsuitable in almost a quarter of all patients undergoing surgery. No strong clinical predictors for O&C were found, stressing the need for better preoperative imaging modalities. Survival in these patients is limited, but the majority could be treated with palliative chemotherapy resulting in survival of almost 1 year. 206

4 Open & close procedures in patients with peritoneal carcinomatosis Background Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is currently the treatment of choice in selected patients suffering from peritoneal carcinomatosis (PC) of colorectal cancer (CRC). 1,2 Unfortunately, not all patients with PC are suitable for this treatment. Generally accepted contraindications include the presence of hematogenous metastases to the liver or lungs, advanced age, poor performance status, and widespread peritoneal dissemination mostly defined by a peritoneal carcinomatosis index (PCI) greater than In case HIPEC is not possible, the only remaining treatment option is palliative chemotherapy; feasibility and efficacy of this treatment is currently unknown. 6,7 To select only those patients for explorative surgery who are most likely to benefit from subsequent CRS and HIPEC, all patients diagnosed with PC undergo meticulous preoperative screening. This usually includes laboratory tests, review of pathology reports, assessment of general condition, and radiological imaging to rule out systemic metastases and to assess the degree of peritoneal dissemination. Unfortunately, current imaging modalities, such as CT and PET scan have limited sensitivity for the detection of small metastatic deposits (e.g., in the liver) and usually fail to adequately predict the PCI. 8 As a result, in some patients a decision not to pursue CRS and HIPEC is only taken during explorative surgery and the procedure is then designated as open and close (O&C). Obviously, this is undesirable and should be avoided whenever possible, because it is harmful to the patient but also a burden on hospital resources. Many reports on large patient cohorts undergoing CRS and HIPEC have now been published and the HIPEC procedure is currently well characterized. Surprisingly, very little is known about patients who undergo an O&C procedure while CRS and HIPEC was intended. Since these patients constitute a relevant percentage of PC patients, increased knowledge on this patient category is required. Therefore, the current study aimed to identify risk factors for O&C-procedures and to investigate the results of subsequent palliative treatment. By doing so, the percentage of O&C-procedures may be reduced and individual patients may be adequately counseled concerning palliative treatment options and prognosis

5 Chapter 12 Methods Patients Between April 2005 and November 2013, all consecutive patients with PC of CRC operated at the Catharina Hospital Eindhoven or St. Antonius Hospital Nieuwegein in the Netherlands with the intent to perform CRS and HIPEC were included in this study. Data were extracted from a prospective database, focusing on patient and tumor characteristics, operative characteristics, postoperative outcome, and survival. Cytoreductive surgery and HIPEC Before surgery, all patients were investigated by a surgeon specialized in HIPECprocedures. Previous operation and pathology reports were reviewed and all patients were staged with an abdominal and thoracic CT scan. Additionally, a multidisciplinary team consisting of a medical oncologist, radiologist, gastroenterologist, and oncologic surgeons decided on the appropriate treatment course. In case widespread PC was suspected based on the radiological or clinical findings, a diagnostic laparoscopy was added to the preoperative workup. Patients who were deemed unsuitable for HIPEC by laparoscopy were excluded from the current study. In the patients deemed eligible for CRS + HIPEC, an exploratory laparotomy was performed as described previously. 9 The purpose of every operation was to remove all visible tumor deposits in the peritoneal cavity. O&C was defined as a patient who was initially enrolled for surgery but proved not to be eligible for CRS and HIPEC after exploring the peritoneal cavity. The main reason for discontinuation was noted in the medical chart and included an extensive disease characterized as Peritoneal Cancer Index score >20, 10 and/or spci > 5, 11 massive small bowel involvement resulting in short-bowel syndrome if resected, liver metastases, or inability to radically resect the primary tumor. In patients in whom cytoreduction was feasible, completeness of cytoreduction was scored using the R-score (R-1: no macroscopic disease, R2a: residual tumor nodules 2.5 mm in diameter, R2b: residual tumor nodules between 2.5 mm and 2.5 cm in diameter). HIPEC-procedures were performed by using the open-colosseum technique. Saline was heated and infused until a temperature of C was obtained, followed by adding Mitomycin C (35 mg/m 2 ), which was circulated for 90 min using the Performer HT (RanD Biotech, Italy). 208

6 Open & close procedures in patients with peritoneal carcinomatosis Statistical analysis Patient and tumor characteristics were compared and analyzed using a Chi square or Fisher s exact test according to sample size. Student t test or Mann Whitney U was used in case of continuous variables. All tests of statistical significance were twosided. Kaplan Meier was used to analyze survival. P < 0.05 was considered statistically significant. Logistic regression analysis was performed to find predictors of becoming O&C, including only variables that proved to be significant in the univariate analyses. To find factors influencing survival after O&C, Cox-regression analysis was used. For COX analyses and logistic regression, P < 0.10 was considered statistically significant. Data were analyzed using the statistical package for social sciences (SPSS Inc., Chicago, IL), version Results In total, 350 patients were included in the current study (Table 1). In 82 patients (23.4%), CRS and HIPEC was deemed impossible after exploring the abdominal cavity ( O&C ). Reasons for discontinuation of the procedure were a PCI scored > 20 (50% of O&C), an irresectable primary tumor (29.3%), massive small-bowel involvement (14.6%), and presence of unexpected liver metastases (6.1%). Seventeen among these 82 had prior diagnostic laparoscopy (17%). Before referral, 318 patients (90.9%) had undergone previous surgical intervention. In 250 patients (71.4%), the primary tumor had already been removed. There were no differences in the surgical intervention percentage (91.5 versus 92.5%, P = 0.75) or the primary tumor resection rate (70.7 versus 71.6%, P = 0.87) between the openclose and CRS + HIPEC groups. Also when excluding metachronous PC patients, who all had previous primary tumor resection, no statistically significant results were seen (P = 0.86 and 0.39, respectively). At presentation in our centers, 28 (34.1%) patients in the O&C group had a colostomy compared with only 59 (22%) in the CRS + HIPEC group (P = 0.03). The interval between primary intervention and exploratory laparotomy did not statistically differ between either the synchronous (2.2 versus 2.1 months, P = 0.24) or metachronous (20.8 versus 20.3 months, P = 0.66) O&C and CRS + HIPEC group. Regarding the ASA classification, 14 patients (18.7%) in the O&C group were ASA III compared with only 23 (8.7%) in the CRS + HIPEC group (P = 0.02)

7 Chapter 12 A similar percentage of patients received neoadjuvant chemotherapy (7.3 versus 10.8%, P = 0.36) before referral and adjuvant/palliative chemotherapy after intervention (74.7 versus 69.5%, P = 0.20). Table 1, General characteristics (N = 350) Variable Open-close (%) CRS + HIPEC (%) P value N = 82 (23.4) N = 268 (76.6) Gender (%) Male 51 (62.2) 129 (48.1) 0.02 Female 31 (37.8) 139 (51.9) Reason open-close (%) PCI 41 (50.0) Small bowel 12 (14.6) Irresectable process 24 (29.3) Liver metastases 5 (6.1) PC type Synchronous (%) 56 (68.3) 149 (55.6) 0.03 Metachronous (%) 26 (31.7) 119 (44.4) Surgical intervention (%) 75 (91.5) 248 (92.5) 0.75 Synchronous only (%) 49 (87.5) 129 (86.6) 0.86 Metachronous only (%) 26 (100) 119 (100) Primary tumor resection (%) 58 (70.7) 192 (71.6) 0.87 Synchronous only 32 (57.1) 75 (50.3) 0.39 Metachronous only 26 (100) 119 (100) Presence of ostomy (%) 28 (34.1) 59 (22.0) 0.03 Interval primary surgery HIPEC (mo) Synchronous 2.2 ( ) 2.1 (0 32.6) 0.24 a Metachronous 20.8 ( ) 20.3 ( ) 0.66 a ASA score (%) I 6 (8.0) 28 (10.6) 0.02 II 54 (72.0) 214 (80.8) III 14 (18.7) 23 (8.7) IV 1 (1.3) 0 Neoadjuvant chemotherapy (%) 6 (7.3) 29 (10.8) 0.36 Adjuvant/palliative chemotherapy (%) 59 (74.7) 173 (69.5) 0.20 a Mann Whitney Tumor characteristics In both the O&C and CRS + HIPEC group, the majority was diagnosed with a T4-tumor at initial presentation (45.1 and 48.5% respectively, P = 0.74). The percentage of N2 nodal stage was 29.3% in the O&C group compared with 38.1% in the CRS + HIPEC 210

8 Open & close procedures in patients with peritoneal carcinomatosis group. There was no statistical difference in N-stage distribution, although in 33 cases (9.4%), nodal stage was unknown. Tumor differentiation significantly differed between both groups, as more poorly differentiated tumors were present in the O&C group (44 versus 22.8%) and consequently, less moderately differentiated tumors (40 versus 64.3%, P = 0.01). Signet cell differentiation (8 versus 8%) and mucinous histology (30 versus 25.6%, P = 0.45) were similar in both groups. Regarding the localization of the primary tumor, the right colon area appeared to be the origin in the majority of patients (41.1%). No statistical differences were found in localization between both groups. Tumor characteristics are shown in Table 2. Table 2, Tumor characteristics Variable Open-close (%) CRS + HIPEC (%) P value N = 82 (23.4) N = 268 (76.6) T stage (%) T1 0 (0) 2 (0.7) 0.74 a T2 3 (3.7) 10 (3.7) T3 26 (31.7) 116 (43.3) N stage (%) N0 13 (15.9) 77 (28.7) 0.10 a N1 27 (32.9) 74 (27.6) N2 24 (29.3) 102 (38.1) Nx 18 (22.0) 15 (5.6) Tumor differentiation (%) Good 4 (4.9) 13 (4.9) 0.01 a Moderate 20 (24.4) 144 (53.7) Poor 22 (26.8) 51 (19.0) Signet cell 4 (4.9) 16 (6.0) Unknown 32 (39.0) 44 (16.4) Mucinous (%) Yes 21 (25.6) 68 (25.4) 0.45 No 49 (59.8) 198 (73.9) Unknown 12 (14.6) 2 (0.7) Localization of primary tumor Right colon 39 (47.6) 105 (39.2) 0.55 Transverse 5 (6.1) 13 (4.9) Left colon 2 (2.4) 17 (6.3) Sigmoid 29 (34.1) 99 (36.9) Rectum 7 (8.5) 32 (11.9) Unknown primary 1 (1.2) 1 (0.4) 12 a Including patients with known pt, pn, differentiation, and mucinal status 211

9 Chapter 12 Following CRS + HIPEC, 96.6% of patients had a macroscopically complete resection (R1). In total, 125 patients ended up having a colostomy after the procedure. This was similar in both groups (36.6 versus 35.4%, P = 0.83). Thirty-day mortality occurred in three patients in each group (3.7 versus 1.1%, P = 0.14). Risk factors for O&C Table 3 provides odds ratios for an O&C procedure. The presence of a colostomy before HIPEC increased the risk for O&C (odds ratio (OR): 2.03, range , P = 0.06). Also, an ASA score of 3 was associated with an increased risk for becoming O&C (OR: 4.35, range , P = 0.04). Female patients was the only factor associated with a decreased risk of becoming O&C (OR: 0.56, range , P = 0.10). Table 3, Risk factors for inability to perform CRS + HIPEC Variable P value Odds ratio 95% CI PC dx Synchronous 0.80 Ref Ref Metachronous Gender Male 0.10 Ref Ref Female Differentiation Good 0.14 Ref Ref Moderate Poor Signet Ostomy at presentation No 0.06 Ref Ref Yes ASA I 0.66 Ref Ref II III Treatment Open & Close Sixty-seven (81.7%) of the 82 patients in the O&C group had explorative surgery only. In the remaining group, ten (12.2%) had some form of resection (mostly low-anterior resection or omentectomy) and five (6.1%) had bowel diversion surgery. Postoperatively, 59 patients (74.7%) received palliative chemotherapy after hospital discharge. Median 212

10 Open & close procedures in patients with peritoneal carcinomatosis survival in this group was 11.2 months (95%-CI ) compared with 2.7 months (95%-CI ) in those not receiving palliative chemotherapy (P < 0.001). Survival analysis Overall survival in the O&C group was 9.8 months with no 5-year survival reported versus 31.0 months in the HIPEC group (P < 0.001, Figure 1). Median survival did not statistically differ between synchronous or metachronous PC (7.8 versus 10.5 months, P = 0.11). When comparing the reasons for discontinuation, survival was 7.0, 6.5, 17.2, and 14.5 months for advanced PCI, irresectable primary tumor, massive smallbowel involvement and presence of liver metastasis respectively (P = 0.67). Within the synchronous O&C group, primary tumor resection did not influence survival (median, 6.5 versus 9.8 months, P = 0.88). Figure 1, Overall survival in the O&C group compared with the HIPEC group Predictors of death in open-close patients are shown in Table 4. Signet cell histology (hazard ratio (HR): 14.7, range , P = 0.08) and ASA 3 classification at exploratory laparotomy (HR: 18.4, range , P = 0.01) were associated with an increased risk of death. On the contrary, primary tumor location in the rectum (HR: 0.04, range , P = 0.02) and administration of palliative chemotherapy (HR: 0.02, range , P < 0.001) had an increased chance of survival

11 Chapter 12 Table 4, Predictors of death within open & close group Variable Hazard ratio 95%-CI P value PC dx Metachronous Ref Ref 0.86 Synchronous Age category (yr) <50 Ref Ref Primary location Right Ref Ref Transverse ,23 Left Sigmoid Rectum Differentiation Good Ref Ref Moderate , Poor Signet Mucinous 0.65 No Ref Ref Yes Primary resection No Ref Ref 0.76 Yes Reason open close PCI Ref Ref Small bowel ,46 Irresectable process Liver metastases ASA score I Ref Ref II , III Stoma post-hipec No Ref Ref 0.24 Yes Palliative chemotherapy No Ref Ref <0.001 Yes

12 Open & close procedures in patients with peritoneal carcinomatosis Discussion This study reports on patients with PC of CRC in whom CRS and HIPEC was intended but was deemed impossible during surgical exploration. The current study shows that despite preoperative screening almost one-fourth of all procedures was discontinued and was designated as O&C. Therefore, this category constitutes a relevant proportion of patients in HIPEC-centers and needs further characterization. The main reason for discontinuing with HIPEC appeared to be an advanced PCI, being responsible for half of the O&C procedures. An increased PCI is an indicator for poor prognosis, although a clear cutoff point for not continuing the procedure cannot be easily determined. Gomes da Silva et al. reported that using a PCI of 20 as a cutoff point marks the difference between median survival of 41 months (PCI < 20) and 16 months survival (PCI > 20). 3 Other groups report cutoff points of 15 or 13 to be important delineators for prognosis. 4,12 More importantly, these authors stress the fact that other factors, such as tumor histology and whether certain parts of the peritoneum are involved or not, should be taken into account when determining eligibility. Consequently, PCI as sole criterion for discontinuation of the procedure is not sufficient. Other factors, such as the possibility of achieving a complete macroscopic resection are equally important to prevent recurrent and ongoing disease. 13 Consequently, a recent article by Cashin et al. showed that even in high-volume disease characterized by PCI > 20, long-term survival is achievable. 14 Nevertheless, in our institutions, PCI > 20 during explorative laparotomy is usually considered a contraindication to pursue CRS and HIPEC and only a few patients with a PCI > 20 were operated. Ideally, the PCI should be determined before surgery by radiological examination. It has been suggested that PET-CT and MRI may contribute to a more accurate assessment of the intra-abdominal tumor burden. However, multiple authors conclude that radiological imaging of peritoneal deposits is of limited help in preoperative assessment of tumor spread and improvement in imaging modalities is therefore much needed in this patient category. 8,15 17 Another important reason for an O&C procedure was the inability to resect all visible tumors. It has been extensively proven by several authors that not achieving a complete resection results in a significantly poorer median survival Yonemura et al. pointed out that another important factor limiting the surgical eligibility is small bowel involvement. They demonstrated that CCR-0 resection rates were significantly higher in patients when the small bowel-pci was below 2 (91.5%) compared with a score above 2 (45.8%,

13 Chapter 12 P < 0.001) and concluded this particular scoring to be an independent prognostic factor. 21 Small bowel involvement also was a significant reason for not being able to perform optimal CRS in our study. In a previous study by Iversen et al., the rate of O&C in patients scheduled for CRS + HIPEC decreased from 48 to 37% after applying routine diagnostic laparoscopy. 22 Currently, we do not perform routine diagnostic laparoscopy in all possible candidates for CRS + HIPEC. This was only performed in case of uncertainty regarding the extent of intraperitoneal spread or resectability. In our study, only a quarter of patients were O&C and only 17% underwent diagnostic laparoscopy before explorative surgery. In these patients, diagnostic laparoscopy apparently failed to predict an O&C outcome. This underlines the difficulty to adequately assess disease spread, as small bowel, mesentery, and the retroperitoneal plane are difficult to evaluate using laparoscopy, especially when adhesions from prior surgery are present. Consequently, laparotomy remains the gold standard to determine the extent of intraperitoneal dissemination. An important finding in the current study is that few variables were significantly different between both groups. A colostomy present before explorative laparotomy and/or an ASA score of 3 were associated with an increased risk of O&C. The fact that only these variables were significant stresses the need for improvement of preoperative workup using diagnostic modalities, which have so far not been sufficient to adequately predict tumor burden as mentioned before. Interestingly, removal of the primary tumor in the synchronous setting did not decrease the chance for subsequent HIPEC. It is however hypothesized that extensive surgery in the presence of PC results in the release of intraperitoneal growth factors and subsequent tumor growth. It is possible that due to the relatively small window between primary intervention and explorative laparotomy, this phenomenon does not yet lead to situations in which CRS + HIPEC cannot be performed. Ideally, the interval is shorter but patients who underwent surgical intervention need time to recover to be in optimal condition to undergo extensive surgery again. 23 Primary tumor resection did not significantly improve survival within the O&C group. Because resection of the tumor is likely to increase the chance for postoperative complications, this may be omitted when the tumor is asymptomatic. Another interesting factor was the fact that signet ring cell histology was associated with an increased risk of death within the O&C group. Poor survival in this particular patient category also has been pointed out by other authors and the question remains whether CRS + HIPEC even has a role in increasing survival. 24,25 216

14 Open & close procedures in patients with peritoneal carcinomatosis Patients with PC in whom HIPEC is not possible may be offered palliative chemotherapy instead. Previous studies have shown survival rates of 6 12 months in similar but smaller patient series The current study reveals that most patients (75%) of the O&C group could be treated with palliative chemotherapy resulting in a survival of almost 1 year after surgery. It should be kept in mind that only patients who can tolerate chemotherapy, based on, among others, general condition and performance status, at this stage receive chemotherapeutic treatment. 29 Nonetheless, this is important information for patients in whom HIPEC is not possible offering guidance in their decision regarding the remaining treatment opportunities. Prevention of this event is preferable, as O&C results in an emotional burden on the patient and uses significant hospital resources. Additionally, decreasing the rate of O&C results in less uncertainty regarding this procedure in patients scheduled for CRS + HIPEC. Conclusions Almost one in four of all patients selected for CRS and HIPEC were found to have irresectable disease at laparotomy. No strong preoperative predictors of irresectablilty could be identified, which stresses the need for better preoperative imaging modalities. Survival in these patients is limited, but 75% of patients may be treated with palliative chemotherapy, resulting in survival of almost 1 year

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